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Executive Summary

Genentech's Activase (alteplase) brand of tissue plasminogen activator, cleared by FDA on Nov. 13, "has the property of fibrin-enhanced conversion of plasminogen to plasmin," according to approved labeling. "When introduced into the systemic circulation at pharmacologic concentration, Activase binds to fibrin in a thrombus and converts the entrapped plaminogen to plasmin," the labeling explains in the key definition of the compound's clot-specific activity. TPA is indicated for three situations in the final labeling: "Activase is indicated for use in the management of acute myocardial infarction in adults for the lysis of thrombi obstructing coronary arteries, the improvement of ventricular function and reduction of the incidence of congestive heart failure." Genentech is touting its TPA product, the first approved for marketing in the U.S., as "clot selective" in an attempt to distinguish the thrombolytic agent from streptokinase, approved one week earlier for treatment of heart attack. "TPA is a very different drug from streptokinase," Burton Sobel, MD, Washington University in St. Louis and a consultant to Genentech, remarked at a Nov. 13 press conference in Washington, D.C. TPA's "own biochemistry makes it much more specific . . . in that it does not degrade circulating proteins whereas it degrades clots," Sobel said. "Streptokinase does not have that discriminatory power." FDA Commissioner Frank Young took a more neutral position towards the two thrombolytic agents. He was asked at a separate Nov. 13 press conference to compare the two products. "They are very close to being the same, [however], when you ask about effectiveness that's a difficult question to answer," Young responded. "Based on the fact that both of them improved the status of the heart, we feel that both of them are likely to be quite similar. But we leave this to the physicians to determine which one he or she feels is most appropriate." Genentech will likely cite TPA's clot-dissolving superiority in the war of the labels as the two I.V. lytic products begin U.S. launches this month. An early study comparing streptokinase and TPA (TIMI I) was halted on ethical grounds when the opening rate of clots in the TPA group was found to be twice as high as those in the streptokinase group. However, a direct correlation between clot lysis and mortality has yet to be shown with TPA. While the new streptokinase labeling mentions the product's efficacy in reducing mortality, approved Activase labeling makes no reference to mortality. "Lysis of coronary artery thrombi has been documented in 71% of patients treated with Activase within six hours of the onset of symptoms," labeling continues. "Improvement of ventricular function and reduction of the incidence of congestive heart failure have been documented in patients treated within four hours of the onset of symptoms." The recommended Activase dosage is 100 mg infused intravenously over three hours -- 60 mg given the first hour, of which six to 10 mg is administered as a bolus in the first one to two minutes, with 20 mg given in each of the following two hours. The product is intended for use in a hospital or cardiac care unit only, and yet recommended for use in ambulances or by paramedic personnel. Activase labeling notes the following situations in which the product is contraindicated: active internal bleeding; history of cerebrovascular accident; recent (within two months) intracranial, or intraspinal, surgery or trauma; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; and severe uncontrolled hypertension. Genentech CEO Robert Swanson said that the company will begin shipping Activase within two to three weeks. While the final price to the trade has not been established, the exec indicated that the cost of Activase in the U.S. would be consistent with prices in the other eight countries where the product is currently marketed -- about $2,000 per dose. While Genentech and the streptokinase marketers (Hoechst and SmithKline) portray the marketing battle between the two products as centered on labeling and clinical trial differences, the real marketing fight may center on price. In fact, the lytic products' fight in 1987-1988 may indicate just how much authority hospital formulary committees have taken in recent years and the relative importance of product differentiation vs. price. Swanson reported that some third-party payors in the state of California have already authorized reimbursement for Activase therapy. The timing of the Activase approval, one week after streptokinase, is opportune by providing Genentech with an opportunity to actively promote TPA at the upcoming American Heart Association annual meeting in Anaheim, California. In addition to symposia scheduled in the near future, a 20-city physician education teleconference is planned for Dec. 1, Genentech said. The approval will also pit the marketing efforts of a relative newcomer to the pharmaceutical industry, Genentech, against the established marketing muscle of SmithKline and Hoechst-Roussel. According to a presentation by Swanson at a recent Robertson Colman analysts meeting, Genentech is in the process of expanding its sales force from 75 to 150 reps, which would give the biotech company a marketing force at least double the size of SmithKline's recently announced specialty acute care cardiology force. ACTIVASE WARNING EXCERPTED FROM FDA-APPROVED LABELING In the following conditions, the risks of Activase therapy may be increased and should be weighed against the anticipated benefits: Recent (within 10 days) major surgery, e.g., coronary artery bypass graft, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels Cerebrovascular disease Recent gastrointestinal or genitourinary bleeding (within 10 days) Recent trauma (within 10 days) Hypertension: systolic BP >=180 mm HG and/or diastolic BP >=110 mm Hg High likelihood of left heart thrombus, e.g., mitral stenosis with atrial fibrillation Acute pericarditis Subacute bacterial endocarditis Hemostatic defects including those secondary to severe hepatic or renal disease Significant liver dysfunction Pregnancy Diabetic hemorrhagic retinopathy, or other hemorrhagic ophthalmic conditions Septic thrombophlebitis or occluded AV cannula at seriously infected site Advanced age, i.e., over 75 years old Patients currently receiving oral anticoagulants, e.g., warfarin sodium Any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location

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